We have used the cloning of cancer-associated chromosomal aberrations as a means of discovering genes that play roles in growth and development. In the past, this strategy led to our discovery of six genes. We characterized the genomic and cDNA structures of each of these six genes and then turned to the functional characterization of a subset of the six. Over the past year, we have successfully generated homozygous "null" animals for the neuronal lineage specific bHLH transcription factors NHLH1 and NHLH2 and for the immediate early response gene SIL, activated at the G0-G1 transition, and implicated in the etiology of T cell ALL when juxtaposed to another bHLH transcription factor discovered in this laboratory (the hematopoietic lineage determiner, SCL). The phenotype of the NHLH2 "knockout" animal is hypogonadal, obese, and sex drive deficient. Both males and females show a disruption of the normal hypothalamic-pituitary axis that controls sexual development at puberty. The female defect appears capable of being bypassed by the presence of normal male pheromones. The SIL knockout animals die between embryonic day 8.5-10.5. The affected fetuses show loss of normal regulation of left-right symmetry of body axis, turning, and cardiac development. The NHLH1 knockout mouse is capable of full embryonic maturation and birth. Analysis of phenotypic characteristics for the NHLH1 "null" animal is just now beginning. We have thus, over the past year, generated three model systems for studying the effect of two bHLH and one immediate early gene on embryonic development, cellular proliferation, and lineage determination. These systems are providing the basis for our next phase of investigations into these issues.